1. Field of Technology
The present invention relates to a p53 variant characterized in that it is capable of transactivating the p21- and 14-3-3σ-promoter but not the mdm2-, bax- and PIG3-promoter. In a preferred embodiment, said p53 variant is characterized in that exon 7, exon 8 and/or exon 9 are partially or entirely deleted. The present invention also relates to means for inhibiting the activity of this p53 variant which is useful for the therapy of cancer. Further increasing the amount of said p53 variant can increase DNA repair by extending the S phase cycle.
2. Discussion of Related Art
Activation of the tumor suppressor p53 after genotoxic insults leads to the induction of downstream events that provide a complex network of signals leading to cell cycle arrest or apoptosis. Both events are in large part due to p53-dependent transcriptional activation of several downstream genes including cell cycle regulators (e.g., p21, 14-3-3σ, Gadd45) and proapoptotic factors (e.g., bax and PIGs). Since both pathways are activated by p53-mediated transactivation of genes, regulatory mechanisms must exist to determine the choice of the appropriate target genes within a given cellular and physiological context. The complex regulatory web that mobilizes p53 after stress is continuously expanding and includes key checkpoint regulators such as the phosphatidylinositol 3-kinase family members ataxia telangiectasia mutated (ATM) and ATM-Rad3-related protein (ATR) as well as the downstream checkpoint kinases Chk2 and Chk1. Phosphorylation on serine (S) 20 of p53 by Chk2/Chk1 helps to stabilize p53 by uncoupling it from the Mdm2 ubiquitin ligase, while ATM/ATR-catalyzed phosphorylation on S-15 participates in the activation of p53.
The p53 tumor suppressor gene is mutated in a large fraction of human cancers, indicating that wild-type p53 (wtp53) function is required to limit tumor growth. Depending on the physiological circumstances, p53 can prevent growth through two mechanisms. First, p53 causes arrest in both the G1 and G2 phases of the cell cycle and second, p53 is involved in the induction of apoptosis. Both events are in large part due to p53-dependent transcriptional activation of several downstream genes including cell cycle regulators (e.g. p21, 14-3-3σ, Gadd45) and pro-apoptotic factors (e.g. bax and PIGs). It is not clear, how the transcriptional activity of p53 is regulated to induce growth arrest or apoptosis. However, distinct posttranslational modifications of p53 such as phosphorylation, acetylation, O-glycosylation, proteolysis and/or binding of p53 to other proteins are most likely required to determine the promoter selectivity of p53. Since so far the mechanisms of selective activation of promoters of genes responsible for cell cycle regulation and apoptosis by p53 are not known, an adequate medical treatment of tumors associated with an aberrant expression or activity of p53 is difficult.
Thus, the technical problem underlying the present invention is to provide means for the treatment of cancer types associated with an aberrant expression/activity of p53.